We appreciate the interest of Dr. Scheller and colleagues in our randomized study comparing everolimus-eluting stents (EES) with drug-eluting balloons (DEB) in patients with drug-eluting stent (DES) in-stent restenosis (ISR) (1). Scheller et al. (2) pioneered the preclinical and clinical studies demonstrating the efficacy of DEB in patients with ISR. However, we respectfully disagree with some interpretations of our findings.

First, the RIBS IV (Restenosis Intra-stent of Drug-Eluting Stents: Paclitaxel-eluting Balloon vs Everolimus-eluting Stent) trial investigators are experts in the treatment of ISR. Indeed, for the last 15 years, this group has been focusing on the treatment of this condition, using different strategies (1,3). Investigators were well aware of the importance of aggressively tackling under-expanded stents and preventing geographic miss phenomena, issues that were re-emphasized in the protocol (1,3). In our study, immediate and late angiographic findings in each arm were similar when results were compared in centers lumped together by tertiles according to the number of treated patients.

Second, optimization of final results was systematically attempted, and the strategy of high-pressure balloon dilation was performed in both arms (1,3). A mean 18 bar was used in the DEB arm, and importantly, the balloon-to-artery ratio was larger in this group. However, suboptimal initial results may still occur after DEB. Indeed, 19 patients (12%) treated with DEB had a residual stenosis of ≥30% (range: 30% to 41%) on quantitative angiography. We tried to avoid crossover that was restricted to only 5 patients with significant residual stenosis or type ≥C dissections. Whether a more liberal crossover to DES would benefit a DEB strategy in this scenario deserves further investigation. Moreover, the mandated aggressive lesion predilation dissipates any potential concern of significant drug loss from the DEB before inflation. Finally, the superior immediate angiographic results of the EES are in line with those of all previous studies comparing balloon with stent-based strategies. Actually, the small difference in minimal lumen diameter after the procedure (EES: 2.22 mm; DEB: 2.10 mm) was unexpected and, if anything, would penalize the EES arm (2). We believe that the challenging substrate of DES-ISR explains the relatively poor angiographic results obtained in both arms despite our optimization efforts.

Third, we designed the trial to prevent “oculo-stenotic” reflex-influenced clinical outcomes. All patients with reinterventions in the DCB arm had ischemia or severely occlusive lesions, justifying the procedure. However, operators were not blinded to treatment allocation, and previous studies suggested that reinterventions would be perceived as less attractive in patients with ISR on a double-metal layer (4). In our study, however, the 8 patients with untreated ISR in the EES arm were completely asymptomatic (1 patient had total vessel occlusion and 7 “moderate” ISR [diameter stenosis: 53 ± 3%; minimal lumen diameter: 1.3 ± 0.3 mm]). Thus, in the EES arm, a significantly larger minimal lumen diameter and smaller diameter stenosis were obtained at follow-up, and of the fewer patients developing recurrent ISR, many were asymptomatic, showing just moderate lesions that were left untreated (1).

Our findings confirm the superior efficacy of DEB in patients with DES-ISR compared with that of previous studies using more classical interventions. However, in this challenging anatomic scenario, EES provided better late angiographic findings and also a significant reduction in the need for reinterventions than DEB (1). We fully agree that long-term safety and efficacy information on these novel interventions are urgently needed. We also consider the “safety signal” favoring DEB rather than “first-generation” DES, detected in some previous ISR trials at very late follow-up, to be of major interest, but this should be interpreted with caution as those studies were largely unpowered in this regard (4). Currently, the real challenge remains to identify the subgroup of patients with DES-ISR in whom DEB will provide long-term results similar to EES.

Footnotes

Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Toolbox

Thank you for your interest in spreading the word about JACC: Journal of the American College of CardiologyNOTE: We request your email address only as a reference for the recipient. We do not save email addresses.

Your Email *

Your Name *

Send To *

Enter multiple addresses on separate lines or separate them with commas.